Peptides and proteins are widely used in medical practice, and since they can be produced by recombinant DNA technology it can be expected that their importance will increase also in the years to come. The number of known endogenous peptides and proteins with interesting biological activities is growing rapidly, also as a result of the ongoing exploration of the human genome. Due to their biological activities, many of these polypeptides and proteins could in principle be used as therapeutic agents. Endogenous peptides or proteins are, however, not always suitable as drug candidates because they often have half-lives of few minutes due to rapid degradation by peptidases and/or due to renal filtration and excretion in the urine. The half-life of polypeptides or proteins in human plasma varies strongly (from a few minutes to more than one week).
A high clearance of a therapeutic agent is inconvenient in cases where it is desired to maintain a high blood level thereof over a prolonged period of time. One way which has been currently used to overcome this disadvantage is to administer large dosage of therapeutic peptide or proteins of interest to the patient so that even if some therapeutic peptide or protein is degraded, enough remains to be therapeutically effective. However, this method is uncomfortable to patients. Since most therapeutic peptides or proteins cannot be administered orally, the therapeutic peptide or proteins would have to be either constantly infused, frequently infused by intravenous injection or administered frequently by the inconvenient route of subcutaneous injections. The need for frequent administration also results in much potential peptide or protein therapeutics having an unacceptable high projected cost of treatment. The presence of large amounts of degraded peptide or protein may also generate undesired side effects.
Discomfort in administration and high costs are two reasons why most therapeutic peptides or proteins with attractive bioactivity profiles may not be developed as drug candidates.
Therefore, one approach to prolong half-life of peptides or proteins is to modify the therapeutic peptides or proteins in such a way that their degradation is slowed down while still maintaining biological activity. Serum albumin has a half-life of more than one week, and one approach to increasing the plasma half-life of peptides or proteins has been to derivatize them with a chemical entity that binds to serum albumin or other plasma proteins.
However, there is still a need to identify new half-life extending moieties to modify therapeutic biomolecules such as peptides and proteins in order to provide longer duration of action in vivo while maintaining low toxicity and therapeutic advantages.